Clinical evidence has shown that selective serotonin reuptake inhibitors (SSRIs) and "atypical" antipsychotics are drugs commonly used and proven effective for the treatment of some of the most important and incapacitating symptoms associated with autism spectrum disorders. SSRIs have been identified by researchers and patients' families as some of the most clinically useful agents, especially in targeting repetitive preoccupations, perseverative behaviors and anxiety-related symptoms. Atypical antipsychotics have also proven effective for improving other types of symptoms such as hyperactivity, and in reducing the frequency and intensity of temper outbursts and aggression in patients with autism. Nevertheless, these currently available drugs still face an undesired side effect profile that limits their use, especially in treating young children. The proposed research program focuses on the synthesis and biological evaluation of novel bi-functional molecules that, by incorporating into one molecular entity the biological effects of both SSRIs and atypical antipsychotics, can provide synergism in terms of their potential efficacy over a wider variety of the core symptoms in patients with autism. In order to develop the proposed bi-functional molecules, we have designed and plan to prepare a series of new drug candidates, which judiciously combine portions of SSRIs with known 5-HT2A receptor antagonists. This is a pilot research study, which represents an innovative approach to the pharmacological treatment of autism. It can be extremely beneficial since it has the strong potential to overcome the drawbacks of two separate pharmacological treatments, which include high costs and undesired side effects. Biological evaluation of the proposed molecules will provide valuable information about the structural features necessary to achieve strong and highly selective binding to both target sites, and give preliminary evidence in regard to whether the new molecules represent valuable "lead" compounds for further in vitro and in vivo investigations. Finally, we believe that this study supports the mission of NIH in its ongoing search for effective treatments for autistic disorder as well as for depressive illnesses, and that the results obtained by this research, will further advance our understanding of autism and lead to improved treatment methods. [unreadable] [unreadable] [unreadable]